12-2, take the win right?

[biopearl123]

I suppose the smart thing is to take the win and move on toward approval, right? But I am troubled. There were still two strong voices who voted against, who will probably continue to be heard as approval moves forward and perhaps be voices in favor of the dreaded “black box” (ok maybe not so dreaded as the important thing is approval). But here are my issues: 1. The committee heard from the experts that the FDA’s attempt to apply the end points of CR/PR/mCR traditionally used to evaluate disease with high % of marrow blasts simply does not apply to L/R MDS because there are very few blasts to evaluate in the bone marrow. They tried to do it anyway and failed to recognize the magnitude of marked changes in TR as the appropriate end point. 2. The FDA tried to apply a standard that is not used in studies of L/R MDS, namely looking at an entire group rather than responders 3. Speaking of responders, the FDA tried to say parts of the study did not use pre specified end points when they did. 4. The FDA and two of the ODAC members dismissed the ability of the experts to properly manage cytopenias and claimed this risk outweighed the benefits of the drug despite the reassurance from the experts to the contrary. 5. The FDA and two of the ODAC members insisted on applying an ancient IWG rubric to assess improvement when in fact, understanding of the disease had evolved and most patients in the study did show HI. They were not willing to wait the extra 8 weeks it took to prove it and that the new IWG standard called for. 6. The profound fatigue associated with current front line therapies prevents a substantial number of patients from even moving to a second dose. Yes, I am troubled that two prominent members of the FDA ODAC, who were not experts in the management of MDS have the voice to impede approval and that the FDA itself did not understand some very basic aspects of how studies in MDS are done and how yardsticks such as CR and PR just do not apply. Thank you Dr. Komrokji and Dr. Savona for setting them straight, but honestly, its the FDA, shouldn’t they already know this? Well, two members of the panel didn’t and perhaps still don’t. We should just take the win and move on.

[bucbeard]

i think we all should be concerned with the FDA potentially issuing a "black box warning", not because it is deserved, but because it appears to be the last card that they hold on behalf of the Big Pharma influences with stakes in this game, that can impact Geron and the development of the game changing Imetelstat in Oncology.

[LWS]

My thoughts --- Perhaps the FDA's role, at this point in the process, is to act as 'devil's advocate' coming out at the gate and starting out with as many negatives as they have heard about. It seems to me that they cannot know everything, in proper perspective, about every new unapproved medicine. That is the job of ODAC and the KOLs (+ patients) who were very informed, leading to the 12 to 2 recommendation.

As far as the two no votes, I believe the Chair (solid cancer oncologist) thought too many non-responsers had to go through the initial disease ( cytopenias -- that could be controlled), and there was no benefit to them. I cannot explain the other no vote (the statistician). The Chairperson was a bit out of his field of expertise (IMO).

I cannot find any example of an ODAC positive recommendation being rejected by the full FDA. A 12 to 2 vote is overwhelmingly positive, especially when the 2 no votes were from non-experts in the field of oncology hematology.

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Yes, I am troubled that two prominent members of the FDA ODAC, who were not experts in the management of MDS have the voice to impede approval and that the FDA itself did not understand some very basic aspects of how studies in MDS are done and how yardsticks such as CR and PR just do not apply. Thank you Dr. Komrokji and Dr. Savona for setting them straight, but honestly, its the FDA, shouldn’t they already know this? Well, two members of the panel didn’t and perhaps still don’t. We should just take the win and move on. --- from bp

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These were the no votes (12 yes, 2 no)

2. AC-Ravi Madan(Chair) NO
8. AC-Mark Conaway NO

As I remember some of the no reasons were:

1. Only a subset of people benefitted
2. Unnecessary disease in those that did not benefit
3. No biomarkers
4. Quality of life (feeling better) is too subjective to be considered

However, all agreed that transfusion independence was an important goal.

It was surprising that the Chair voted no. ---- from LWS

[LWS]

Everyone agreed (including the 2 NO ODAC votes) that Transfusion Independence was important. Imetelstat is not the "perfect" blood cancer medicine, but it is "very good" in many situations and is needed now by patients and it is unique. In combinations (research for many years to come) with important synergies in preclinical testing established and 2 ways to kill cancer stem cells, "very good" will be a very conservative way of describing this medicine. The FDA has no reason to reject ODAC's positive recommendations at this point in the approval process.

Note: CKTC found 2 cases that the FDA rejected after an ODAC positive recommendation. What were the medicines for? When were they rejected, and what was the safety profile? Imetelstat has a good safety profile for such a powerful blood cancer medicine.

[huntingonthebluffs]

Thanks biopearl123 for all your time, efforts and attention to detail. You have again laid out several really important points/observations from the ODAC meeting on 3/14. As usual, you have taken the high road and we all admire your character and discipline in that regard. I for one, prefer to take the high road also, but I fail there often, but almost always when something is not right, especially when it comes to something I consider extremely important.

The FDA consists of smart people as do the committee members voting, including the two no votes. Maybe there is no option but to take the win and move on. But I’m not so sure it isn’t much more than a 1-1 tie between FDA vs Geron at this point given the FDA’s presentations and disposition. If possible, I think biopearl123 preferably or someone on the board with similar knowledge, experience and ability could write an “open” letter to the FDA regarding our collective thoughts and concerns regarding the ADCOM and ODAC presentations and voting. As well as any other future actions that could possibly be taken by the FDA due to their obvious misalignment with the facts and analysis of the CT data and KOL / patient statements.

However on the other hand, the FDA could make up for part of their misalignment by approving Imetelstat months earlier that the PDFUA date of June 16th.

[biopearl123]

Hi Hunt, I think your letter is a great idea but I would say coming to the important conclusions that the FDA is tasked with making, is an evolutionary process. For example, if the ODAC were given the FDA position paper and then asked to vote before they heard Geron’s presentations, how do you think the vote would have gone? I think minds were changed during the meeting itself. Geron’s presentations were that good. And I think the head honcho director of the FDA itself is probably “tuned in” to these meetings. It’s interesting to me that the depth of understanding (in this one small area) we have developed on this board may actually exceed that of a general oncologist who has a million other cancers to treat, and perhaps others within the FDA structure (10s of thousands of employees, some of whom also might have had their minds changed.) I think many prosecuting attorneys no matter what comes out of their mouths in court, have listened to the defense as part of the process. The defense might actually convince them the client they are prosecuting is innocent but they have a job to do, hence the star chamber we witnessed in full force on March 14th. What I am saying is that this is a process and peoples minds change with education. I did write to the FDA during the open comments period (Fish Sr. made me do it) and they published my thoughts. In reality we had one non medical person (FDA employee I think) in the form of a statistician vote against and one non hematologist vote against. Ask yourself if you would actually go to either one for treatment. Me neither. And yes approval before June 16th seems very likely and Geron has plans in place to bolt out of the starting gate when that happens. Thanks for your posts as always, bp

[LWS]

The benefits of Imetelstat out weigh the risks (not even close)

All of the important negatives are temporary and reversible for both responders and non-responders. Obviously, more research is required (partners are a consideration), but that is not a reason to deny it to those who can benefit today from this unquestionably effective medicine, for sick patients with a unique opportunity to regain their health. Imetelstat is powerful as a standalone medicine, and its potential in combinations and IMET2.0 (improved medical chemistry) is vast. Data is still being collected (EAP), and patients are currently benefitting (transfusion independence, quality of life, survival time). JS said the EAP can be considered as an ongoing phase 4.

[LWS]

We know exactly what will happen. ODAC has recommended Imetelstat (March 14th) and the FDA always accepts overwhelmingly positive votes (12 YES votes from blood cancer oncologists, 2 NO votes from others). This is not controversial. Imetelstat kills cancer stem-cells in 2 ways and is needed now by suffering patients. It works now and is a vital building component for future treatments and cures.

[huntingonthebluffs]

Thanks, biopearl123 for your excellent thoughts on the possible impacts on the FDA because of the ODAC meeting. You are on point for sure that it is an evolutionary process and people’s minds are changed with education. I am hopeful the FDA will approve MDS ahead of the PDUFA date of June 16 as they should IMO, but I don’t think the odds are 100%. And I also know that the FDA could complicate the approval with various, but again IMO they shouldn’t and the odds aren’t 0% they won't. Maybe my glasses are just to rose colored, it’s happened to me before, but while the FDA may have a right and need to play the devil’s advocate role, I don’t believe there was justification for misconstruing the facts on AE’s or misusing statistics to water down the various strengths and stellar results of the CTs. And unfortunately, unlike a court of law, they are both the prosecution and judge. I leave some leeway for misunderstanding and ignorance of the disease etc. for the two no votes, but the FDA has had many years and over a decade working with Geron in regards to MDS and MF, so I can’t buy that those in the FDA that should know are maybe just now beginning to understand the key metrics that should be used in determining efficacy and safety, etc.

I think the Geron team is doing a great job while taking the high road, as they must. It has to be frustrating in view of what is IMO clearly unprofessional, possibly sinister tactics being used by the FDA which were in so object indifference to the doctors in the field stating their opinions on efficacy and safety, and patient QOL experiences and Geron’s patient, methodical, professional and medical efforts to bring this needed drug to the market.

I don’t think I’m overreacting when I say there is clearly something way off in a US Government Agency that is crucial to our well being. One can connect the dots anyway one may want but I believe it is undeniable. I hope that those who have influence remain diligent and step up wherever they should to get this approval safely and unencumbered across the line.

BTW, biopearl123, it doesn’t surprise me that you are still communicating in some way with Fishermangents Sr. and I’m sure he is extremely proud of the stellar manner in which you have so admirably carried on the www.Imetelstat.info and ImetelChat endeavors. Your contributions to this board and in battling these diseases are undoubtedly well known far and wide.

[huntingonthebluffs]

I cringe to think what the FDA would have done absent the ODAC and the 12-2 vote. I originally thought the ODAC was basically just another FDA hurdle they would misuse to create additional issues for Geron/Imetelstat on their path to commercialization. While I was likely right regarding the FDA’s intent, I obviously was totally wrong regarding the results. I suspect there are some in the FDA that are frustrated with what happened regarding the reception to their detailed and well laid out presentations and the opposite response to their “findings” from the voting panel. And IMHO, Geron would have received a CR letter prior to the June 16th PDUFA without the ODAC and leaving the FDA to their own devices.

I think I now understand why Geron/Imetelstat wasn’t given priority review and why the FDA’s past actions over the years seemed so out of step with their interpretations of the Imetelstat results, the well understood AE’s and their short term impacts, hematologic improvement erythroid (HI_E), blood supply impacts, QOL impacts to TI patients and even to a degree those that did not reach TI for 8 weeks or more, etc. Can we just chalk this all up to the FDA using 2006 IWG criteria that are nearly two decades old vs current understanding as of at least 2018, etc.? Was it due to their need to be the devils advocate? Are they just out of touch?

Well they have had at least 10 years to come up to speed. There are so many presentations by so many KOLs, so many papers by so many specialists and researchers in the field, so many statements and recommendations by so many doctors who have treated thousands of patients, so many patients testimonies, so many ASH, EHA and other conference posters and presentations, 2-3 rewrites of the 2006 IWG criteria, etc. So we should all ask how is it possible the FDA and their many bright minds could not know. If one can assume that the FDA should not have been so ‘obsolete’ in their understanding, someone should come to task as hundreds of thousands of patients have died in those 10 years that could have benefited and science advanced immeasurably. I am excited that we may see this drug soon commercialized but at the same time it is a major tragedy for such an important government agency to be unable to execute fairly and effectively and has withheld the expeditious trial and availability of Imetelstat to patients in various blood cancer diseases.

[LWS]

The side effect dangers (specifically Cytopenias and Nuetropenias) were discussed on March 14th. ODAC and others (blood cancer experts) put this problem into proper prospective (manageable and can be eliminated in a short time). The problem seems to be that not all benefit. The side effects can be managed and eliminated. This is a case where 'the perfect is the enemy of the good'. The benefit clearly out-weights the risk.

Imetelstat is proven to be a very good medicine, where many patients benefit now, and many more will benefit from combinations (years of new research). Imetelstat is in a class by itself, with vast potential going forward. An ODAC positive recommendation (as far as I can tell) has never been rejected by the FDA. 12 YES is overwhelming.

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by huntingonthebluffs (April 17)

I am excited that we may see this drug soon commercialized but at the same time it is a major tragedy for such an important government agency to be unable to execute fairly and effectively and has withheld the expeditious trial and availability of Imetelstat to patients in various blood cancer diseases.